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Separation method of impurities in angiotensin receptor antagonist and NEP inhibitor compound

A receptor antagonist, angiotensin technology, applied in the field of separation of impurities in complexes, achieves the effect of simple process, accurate and reliable separation method and good reproducibility

Active Publication Date: 2016-09-07
LIANGJIANG MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there is no relevant report on the separation of impurities in the complex of angiotensin receptor antagonist and NEP inhibitor

Method used

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  • Separation method of impurities in angiotensin receptor antagonist and NEP inhibitor compound
  • Separation method of impurities in angiotensin receptor antagonist and NEP inhibitor compound
  • Separation method of impurities in angiotensin receptor antagonist and NEP inhibitor compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] according to figure 1 The flow chart shown is to prepare a complex of angiotensin receptor antagonist and NEP inhibitor, figure 1 This is a flow chart of the preparation process of the complex of angiotensin receptor antagonist and NEP inhibitor provided in Example 1 of the present invention:

[0091] The compound having the structure shown in Formula 4 is a commercially available product.

[0092] 10g of the compound having the structure represented by formula 4 and 1.9g of sodium hydroxide are reacted in water at 20-30°C for 1 hour to obtain the compound having the structure represented by formula 3;

[0093] 10 g of the compound having the structure shown in Formula 3 and 2.6 g of calcium chloride are reacted at 60 to 70° C. for 2 hours to obtain the compound having the structure shown in Formula 2;

[0094] 15 g of the compound having the structure shown in formula 2 and 52 g of 1N hydrochloric acid were reacted at 20-30° C. for 2 hours to obtain the compound having the stru...

Embodiment 2

[0098] The complex of angiotensin receptor antagonist and NEP inhibitor prepared in Example 1 of the present invention was used for impurity separation by high performance liquid chromatography. The column filler in the high performance liquid chromatography was octadecyl Silane-bonded silica gel, the mobile phase includes a phosphate buffer (aqueous phase) with a molar concentration of 35mmol / L and a mixture of acetonitrile and methanol (organic phase) with a volume ratio of 55:45, phosphate buffer and acetonitrile and methanol The initial volume ratio of the mixed solution is 50:50, the flow rate of the mobile phase is 1mL / min, the column temperature is 35°C, and the detection wavelength is 250nm; the gradient elution method is used to make the mobile phase pass through the chromatographic column. The method is specifically as follows: in 0-35min, the volume content of the water phase in the mobile phase is reduced from 50% to 10%, and the volume content of the organic phase i...

Embodiment 3

[0110] The complex of angiotensin receptor antagonist and NEP inhibitor prepared in Example 1 of the present invention was used for impurity separation by high performance liquid chromatography. The column filler in the high performance liquid chromatography was octadecyl Silane-bonded silica gel. The mobile phase includes a 0.1% aqueous solution of trifluoroacetic acid (aqueous phase) and a mixture of acetonitrile and methanol (organic phase) with a mass ratio of 50:50, trifluoroacetic acid aqueous solution and acetonitrile and methanol The initial volume ratio of the mixed solution is 55:45, the flow rate of the mobile phase is 0.8mL / min, the column temperature is 25°C, and the detection wavelength is 250nm; the gradient elution method is used to make the mobile phase pass through the chromatographic column. The specific method is as follows: at 0~35min, the volume content of the water phase in the mobile phase is reduced from 55% to 5%, and the volume content of the organic p...

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Abstract

The invention provides a separation method of impurities in an angiotensin receptor antagonist and NEP inhibitor compound. The method is as below: separating impurities in pharmaceutical composition containing angiotensin receptor antagonist and NEP inhibitor by HPLC method. A mobile phase in the high performance liquid chromatography includes an aqueous phase and an organic phase; the aqueous phase comprises a phosphate buffer solution, trifluoroacetic acid solution or formic acid solution; the organic phase contains an organic mixture or acetonitrile; the organic mixture includes acetonitrile and methanol; and the aqueous phase and organic phase are in the volume ratio of (45%-65%):(55%-35%). The invention adopts the high performance liquid chromatography for separation of impurities; the mobile phase used in the high performance liquid chromatography includes aqueous phase with specific components and the organic phase, and the mobile phase can effectively separate impurities in the angiotensin receptor antagonist and NEP inhibitor compound.

Description

Technical field [0001] The present invention relates to the technical field of complexes of angiotensin receptor antagonists and NEP inhibitors, in particular to a method for separating impurities in the complexes of angiotensin receptor antagonists and NEP inhibitors. Background technique [0002] Angiotensin receptor blockers (ARBs, angiotensin II antagonists) can prevent angiotensin II from binding to its receptors on the blood vessel wall, resulting in lower blood pressure. Because of its ability to inhibit AT1 receptors, such antagonists can be used to fight hypertension, or to treat congestive heart failure and other indications. Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc-containing metalloprotease, which can cleave peptide substrates on the amino terminus of various hydrophobic residues. NEP inhibitors (neutral Endopeptidase inhibitor (NEPi) can reduce the plasma level of ANP, so it can promote natriuresis and has a diuretic effect....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/34
CPCG01N30/02G01N30/34G01N2030/027
Inventor 张磊石功名张小娇孙丹李俊平贺耘
Owner LIANGJIANG MEDICINE CO LTD
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